Principios que rigen la indemnización de los daños

Stepwise uni-variate linear regression analysis was performed in a model including: gen- der, age, radiotherapy, multiple operations, ACTH-deficiency, TSH deficiency, LH/FSH deficiency, GH deficiency, multiple pituitary deficiencies and visual defects as indepen- dent variables, and the questionnaire items as dependent variables.

Age was an independent predictor for reduced physical ability (NHP, standardized β = 0.48, P<0.01) and reduced physical function (SF-36, standardized β = 0.48, P < 0.01). The presence of multiple hormonal deficiencies was an independent predictor for role limita- tions due to physical problems (SF-36, standardized β = 0.28, P < 0.05), impaired social functioning (SF-36, standardized β = 0.29, P < 0.05) and sleep (NHP, standardized β = 0.25, P < 0.05) and increased general fatigue (MFI-20, standardized β = 0.24, P< 0.05). LH/

Table 2. Quality of Life parameters (HADS, MFI-20, NHP, SF-36) in treated NFA patients compared with

controls and age-adjusted reference values NFA patients (n = 99) Controls (n = 125) p-value1 _Age-adjusted reference values 2 p-value3 HADS Anxiety Depression Total MFI-20 General fatigue Physical fatigue Reduction in activity Reduction in motivation Mental Fatigue NHP Energy Pain Emotional reaction Sleep Physical mobility Social isolation SF-36 Physical functioning Social functioning

Role limitations due to physical problems Role limitations due to emotional problems Pain

General health perception Health change 5.00±3.77 4.39±4.44 9.39±7.49 11.26±5.48 10.68±5.08 10.19±5.12 9.58±5.01 9.83±5.04 27.48±39.59 10.24±22.36 15.24±23.01 18.04±26.77 10.28±19.11 10.54±22.17 79.04±22.65 78.97±22.92 65.00±40.18 69.07±39.75 81.28±20.72 57.32±24.25 50.26±22.92 3.80±3.18 3.12±2.63 6.90±5.10 8.00±3.82 7.86±3.72 7.30±3.40 7.71±3.61 7.41±3.78 4.53±16.26 5.20±14.29 4.37±13.00 9.22±19.59 4.76±11.45 1.02±5.29 86.37±17.30 93.66±12.39 86.99±27.41 89.46±24.60 86.58±17.95 70.33±15.63 51.82±16.05 =0.01 <0.01 <0.01 <0.001 <0.001 <0.001 <0.01 <0.001 <0.001 ns <0.001 <0.05 <0.01 <0.001 <0.01 <0.001 <0.001 <0.001 ns <0.001 ns 5.04±3.64 3.79±3.42 8.41±6.31 9.92±5.18 8.79±4.91 8.68±4.62 8.24±4.03 8.26±4.79 15.81±25.54 10.72±18.42 9.01±16.21 18.94±25,01 9.48±13.93 5.83±16.02 71.69±25.24 85.12±22.38 73.66±39.14 84.43±31.36 76.30±26.55 64.93±22.49 48.94±18.04 ns ns ns ns <0.01 <0.05 <0.05 <0.05 <0.01 ns <0.05 ns ns ns ns <0.05 <0.05 <0.001 ns <0.05 ns 1 _{patients compared with own controls.}

2 _{derived from references 18-22.}

Quality of life is decreased in patients treated for nonfunctioning pituitary macroadenoma 87

FSH deficiency was an independent predictor for reduced activity (MFI-20, standardized β = 0.28, P < 0.05) and increased physical fatigue (MFI-20, standardized β = 0.25, P < 0.05). Female gender was an independent predictor for increased anxiety (HADS, standardized β = 0.35, p < 0.05). Radiotherapy, visual field defects and GH deficiency were not found to be independent predictors for reduced QoL in any of the questionnaires.

DISCUSSION

The data in this study indicate that quality of life is reduced in patients successfully treated for NFMA. According to the parameters tested by the HADS, MFI-20, NHP and SF- 36 questionnaires, patients reported a decreased QoL in 10 out of 21 subscales, compared with both age-adjusted reference values and controls. Almost all subscales of the MFI-20, assessing energy/fatigue, showed a significant decreased QoL. Linear regression analysis revealed the presence of multiple pituitary deficiencies, and, to a lesser extent age, as the predominant predictors of a decreased QoL.

In the present study, NFMA patients were compared with own controls and age-adjust- ed reference values derived from literature. The advantage of using own controls is that they are from the same geographic area and socio-economic class as the patients (32). However, these controls might be subject to a selection bias, because patients might have chosen controls with a supposed good health status (33). To overcome this potential bias, we also compared the NFMA patients to age-adjusted reference values from the literature. Moreover, the use of two different control groups might lead to more credible results if the results are consistent (32). The scores of the NFMA patients showed an impaired QoL in more subscales of the four questionnaires, compared with own controls than compared with the age-adjusted reference-values, confirming the possible difference in health status between the two groups. Nonetheless, even compared with the reference data obtained from the literature, our NFMA patients scored worse, supporting our conclusions with respect to the negative effect of NFMA on QoL. Although the response rate in our series of patients with NFMA was 91%, and completed questionnaires were received of 77% of the patients, it seems unlikely, that the non-responders have influenced the outcome of our study, because there were no differences in patient characteristics between respond- ers and non-responders/decliners.

Literature on QoL in patients with NFMA is scarce. To our knowledge only two studies evaluated QoL in NFMA patients (11;14). Johnson et al. reported a reduced QoL in NFMA patients, before treatment, using the SF-36 questionnaire, compared with scores from the normal population (11). Other reports on QoL in NFMA, consisting of heterogeneous groups of patients with both functioning and nonfunctioning tumors, showed a reduced QoL in patients with pituitary tumors in general (15;34;35). However, it was not possible

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to perform subgroup analysis in order to estimate QoL specifically in NFMA, because of the small number of patients (15;34). Moreover, the effects of pituitary diseases on QoL cannot simply be generalized for all pituitary diseases. NFMA patients differ from patients with functioning pituitary adenomas in several aspects. NFMA is more prevalent in older and male patients compared with functioning pituitary adenomas (36). Nonfunction- ing adenomas are treated only when tumor size indicates a macroadenoma, whereas treatment indication in functioning adenomas is focused at hormone overproduction in addition to tumor size. Therefore, pituitary tumors in treated NFMA tend to be larger than tumors in patients treated for functioning pituitary adenomas. In accordance, in NFMA patients there is a higher degree of pituitary deficiencies, whereas patients cured from functioning pituitary tumors also suffer from irreversible effects of previous hormone overproduction, as is the case in functioning adenomas such as Cushing’s disease or acromegaly (12;13). Compared with NFMA, QoL in acromegaly patients is clearly de- creased (17). QoL-assessment in heterogeneous groups, consisting of both functioning and nonfunctioning adenomas, may therefore not be an appropriate strategy to assess QoL in patients treated for NFMA.

The study from Page et al. did not reveal a reduced QoL in surgically treated NFMA patients, compared with patients after mastoid surgery (14). The results of the SF-36 questionnaire from these patients after mastoid surgery are summarized in Table 3. These results do not show concordant differences compared with our NFMA patients, pointing toward a general role for medical illness in impaired QoL. However, this also underscores the notion that the SF-36 questionnaire is not disease-specific, i.e. is not specific for the assessment of QoL in patients with pituitary diseases.

Our results point toward a reduced QoL in physical and psychological as well social items. Treated NFMA patients report increased fatigue, both mental and physical, reduced energy and role limitations due to physical problems as well as reduced activity and re- duced motivation. Interestingly, physical functioning seemed not to be affected compared with age adjusted reference values. NFMA patients also report affected emotional reac- tions, role limitations due to emotional problems as well as affected social functioning.

Table 3. Summary of SF-36 results in patients treated for nonfunctioning pituitary macroadenomas and in

patients after mastoid surgery

NFA treated (own data)

Mastoid surgery (14)

Mean age (yr) 62 61

Physical functioning 79 ± 23 71 ± 31 Physical role 65 ± 40 74 ± 40 Emotional role 69 ± 40 83 ± 35 Social functioning 79 ± 23 83 ± 26 Bodily pain 81 ± 21 76 ± 25 Health perception 57 ± 24 68 ± 21

Quality of life is decreased in patients treated for nonfunctioning pituitary macroadenoma 89

Nonetheless, the HADS questionnaire did not reveal any significant difference between NFMA patients and age-adjusted reference values. This finding is in accordance with the report of Korali et al. in which no elevated rates of mental disorders could be found after treatment for NFMA, even in the case of multiple pituitary deficiencies (37).

We could not properly assess the effect of hypopituitarism per se on QoL, because hypopituitarism was present in 93% of all NFMA patients. Although the number of pa- tients with hypopituitarism seems rather high, it is comparable to the percentage (94%) of patients with hypopituitarism presented in a series of consecutive patients treated for NFMA in our hospital (38). The patient population in the present series seems therefore not skewed towards those patients with more severe disease. Hypopituitarism was found to be an independent predictor of reduced QoL in patients treated for Cushing’s disease, affecting both physical and psychosocial items (13). In the present study, the presence of multiple pituitary deficiencies was the most predominant predictor for decreased QoL, pointing toward an important role of pituitary function for optimal QoL. Hormonal sub- stitution therapy does not reproduce the normal plasma hormone profiles of healthy individuals. Moreover, the effects of hormones in general are difficult to quantify at the tissue level. Consequently, titration of endocrine replacement therapy is possible only within certain physiological limits. These intrinsic imperfections in endocrine replace- ment therapy may result in subtle physiological derangements. Most importantly, this im- perfection in endocrine substitution may result in a decreased QoL. In this study LH/FSH deficiency was an independent predictor for reduced activity and increased physical fa- tigue. This may reflect the lack of sensitive signs and symptoms for monitoring adequacy of testosterone and estrogen substitution (39). We did not measure routinely levels of dehydroepiandrostenedione (DHEA). However, we recently documented in a random- ized placebo-controlled trial, that DHEA substitution superimposed on GH-substitution did not substantially improve QoL in patients with secondary adrenal failure (40). In this study, female gender was an independent predictor for anxiety. The predisposition for female gender as an independent risk factor for a decreased QoL is unclear, and has been previously described in patients with primary brain tumors (41). However, it does not seem to be a disease specific phenomenon given the fact that QoL studies in nonpituitary diseases (malignancies, coronary heart disease, inflammatory bowel disease) also report decreased QoL in female patients as compared with male patients (41-45).

GH deficiency was not found to be an independent predictor for any of subscales of the four questionnaires. In our study only 51% of all GH deficient patients received rhGH substitution. We could not detect a beneficial effect of rhGH substitution on QoL scores. However, this study was, in strict sense, not designed to assess the effect of rhGH substitution on QoL. A recent meta-analysis on the effect of rhGh substitution on various QoL subscales, suggested that rhGH substitution does not improve QoL compared with placebo (46). Moreover, several studies report an improved QoL and well-being (47-50),

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suggesting that in selected patients rhGH substitution may have a beneficial effect on QoL (51).

The four health-related questionnaires used in this study, were not disease-specific, i.e.

they were not developed to assess QoL in NFMA, although the NHP is frequently used in patients with pituitary disease. However, we found a reduced QoL in the majority of sub- scales of the MFI-20, the SF-36 and the NHP. This seems to point toward a strong overall effect of the pituitary diseases on general health and well being of both the physical and the psychosocial aspects.

In conclusion, Quality of Life is reduced in patients after successful treatment of NFMA. According to the MFI-20, NHP and SF-36, patients reported a decreased QoL in almost all subscales compared with age-adjusted reference values and controls. The presence of multiple pituitary deficiencies was the predominant predictor for a reduced QoL.

Quality of life is decreased in patients treated for nonfunctioning pituitary macroadenoma 91

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